HUE034442T2 - Artificial tear emulsion - Google Patents

Artificial tear emulsion Download PDF

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Publication number
HUE034442T2
HUE034442T2 HUE11715556A HUE11715556A HUE034442T2 HU E034442 T2 HUE034442 T2 HU E034442T2 HU E11715556 A HUE11715556 A HU E11715556A HU E11715556 A HUE11715556 A HU E11715556A HU E034442 T2 HUE034442 T2 HU E034442T2
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HU
Hungary
Prior art keywords
emulsion
weight
polymer
lipid
notably
Prior art date
Application number
HUE11715556A
Other languages
Hungarian (hu)
Inventor
Claude Claret
Martine Claret
Carole Gard
Weissenborn Nicola Lamprecht
Original Assignee
Horus Pharma
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Publication date
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Publication of HUE034442T2 publication Critical patent/HUE034442T2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics

Description

Thé present invention relates to lipid enudsions, Ih particular, to artificial tear ©muislons, comprising s raucomimetle .polymer, to the use thereof and to 3 method for obtaining seme· The present invention relates more specifically to the use of these sontpositlens in the ophthalmic domain. Those compositions may more particularly be used for the prevention or the treatment of ocular dryness and/or of disorders linked to; this ocular dryness. These compositions may also be intended for the transport of acbve substances, in particular, in the eye.
The ocuiar surface is a transitional mucous membmne between the externa! environment and the intraocular structures, eyelids constitute the first line of defence for the ocuiar sur face and are involved in the maintenance of the lachrymal ihm which covers the conjunctival epithelium., notably by means of the lachrymal glands and the Meibomian glands situated in the lower end upper eyelids, respectively,
This lachrymal film Is a continuous fluid flirmwith « thickness of between 3 and TO urn and a volume of around TO pit This fiimlis continuously renewed, at a rate of around :! μΙ/οΰη,
Among the functions of the lachrymal filrr», mention may he made olkeeping the ocular surface moist, producing a smooth surface enabling vision without distortion; protecting the cornea and the conjunctive epithelium from, exterior aggressions (irritating materials, dust, bacteria, etc.}., and transporting biological substances used in the physiology of the eye, including oxygen for the cornea.
Furthermore, the lachrymal film is composed of three layers, lipsd, aqueous and mucin;: the lipid layer, of around 100 run in thickness, secreted by the Meibomian glands, which notably reduces evaporation and stabilises the lachrymal film; - the aqueous layer, which nourishes, hydrates and protects the corneo-•conjunctiva! epithelium; besides its high water -cdMifit, :ftl§frilsh: Iff .nutritive? elements, enzymes, antibacterial agents, heahng feefofs and contains a strong mucin concentration gradient; and * the mucin layer, which enables the lachrymal film T he three-layered structure of Été lachrymal fiimsmey tfuftheribe presented; sptOFn having two main phases: a hoh-poiar, hydrophobic phase, in contact with the air and composed of phospholipids, esters, triglycerides and free fatty acids, and * an anionic, polar hydrophilic phase, composed of glycoproteins, lipids, electrolytes., enzymes, polysaccharides and water.
The altering of one of these layers may be at the origin of eye dryness syndrome, for example, due to hyposecretion by the lachrymal glands, or $ malfunctioning of the Meibomian glands, and therefore of the lipid layer of the lachrymal fűm, and leading to .hype r-eva po ration,
Among the symptoms of ocular dryness, mention may be made of pain, itching,, the sensation of a foreign body in the eye, burning, photophobia and general discomfort. Thus, this condition Is disabling and affects the quality of life of patients. furthermore, ocüiärdryn^ss^ of its etiology, ?egq cause keratins and/or conjunctivitis.
This dry n/e ^ybdrome ο* ocular dryness iisqyile eommo« in the pop.qte'ttetj since it is estim«« ed that around IS to 2G% of the population over g§ years of age suffers from it. Moderate end severe forms, involving kerahbs or fcefa^ö»iy^Mttt$fcd%-ifcepr®sent: 2S to 30% of cases.
Itüé'-óf treatment for dry eye syndromes, regardless of the severity, esfopl^ilàêiitff^al-ÂtssfstMtëS, ado known as sMlfidtóMfej •syilÄ.ÄIsi.iy Ä-pn toe symptoms
Historically, Slosple lachrymal substitutes hasad eh sodium chloride have been gradually replaced by solutions based on cellulose derivatives dr carhomers, enabling the viscosity of the solutions to he increased and s: longer lasting Siflbn to be obtained,; However, even more recent ly, two rnajof categories seem to offer greater efficacy: lipid emulsions, and w solutions based « sodianThyafuronat©. Ök-A-39527132 discloses an ophthalmic composition containing an oil-in-water type emulsion comprising a phospholipid and a lipid other than the phospholipid, and? hydroxypropyimethylcelluisss, WO-A-9505.163 discloses lïpld-in-water type bioadhesivs-emulsions containing mucosdhesive macromoieéoíés;
Unfortunately, the vast majority of these solutions hihly address the partial Cesforation of one of Hut components of the lachrymal film.
In particular,, hydrophobic lipid emulsions, act on the hydrophobic or lipid phase of the lachrymal film by limiting hyper-evaporation, whereas the solutions based on mucormmettc hyaluronic acid, act on the hydrophilic phase of the lMhryma?l film and' promote anchoring of the lachrymal film.
Secondly, idee these products must he sterile, a large proportion of the existing solutions comprise preservatives intended to destroy microorganisms after opening and duiridg use of tfre product.
These preservatives may notably be: V toxic or irritating for the ceils of the cornea or conjonctive, the mpcods cells {which release mucins essential for tht^b^ItV'if'tht'lldh'r^pil fiiról or the covering epithelial ceils, and/or source of allergy, inflammation, in particular for chronic pathologies such as glaucoma, allergy or ocular dryness, which require frequent application of products containing preservatives.
Clinical consequences may thus he: an? aggravation of symptoms and/or an evolution towards a chronic disease.
Very dfferg tolatIons contain agents known as surfactants in order to give good?? physicocheodcal stability to the composition. These surfactants may have harmful effects similar to those of preservatives, having an irritating, allergenic or even cytotoxic character. In particular, these: agents, also known as emulsifying agents,; surfactants or wetting agents, present in low quantities, are used to stabilise oil droplets in the oil-based solutions or lipid emulsions, marketed with the Indication of ocular dryness caused by ihype.'-eygporatmn. "hus, existing compositions, may Os insufficiently affective., end may even have undo S; rabig· effects, such es ths destruction of healthy cells, reactivation of the causes of ocular dryness by destabilisation of the lipid layer of the taehcym®* film or allergie reactions. They may also be unstable, requiring specific storage conditions (for example, keep cold., etc.; and/or requiring very frequent use. due to an unsatisfactory cMrsflon of enfin ru
The present Invention thisr&fore aims to resolve ail or some of the : aforementioned problems, in particular, the Invention aims to provide a composition, notably an emulsion, having improved efficacy, free from adverse effects, o? at leas- for which these effects are limited as far as possible, having improved stability, that is easy to obtain, comprising and/or using' during Its production a minimum of deleterious, allergenic, and/or toxic products, and/or having a reconstituting action on the entire lachrymal film.
According to a first:embodiment, thepresem invention relates to an oil-in-water type emulsion free fmmiprsservstite/ofwfekhfthe globules have a maximum sire of less tharusr equal to220:nm, having an psmoiarlty from 110 to ISO mösm/f, comprising: - at least One mucornimetic polymer seieetpd: froth hyafmdoib acids, dektl'Sh sulfate and chondroitin sulfate, at least one phosphriigrd-type ilpid selected from ieosthin% at least one lipid other rhaophosphollpid, at least one stabilising polymer selected from cellulose polymers, citrate buffer medium, water,
Tor Itsiuse in the treatment or prevention of ophthalmic diseases.
The emulsion may comprise: optionally sodium chloride, and optionally: ό an active substance and/or o a substance participating in thi restöratiön of the composition of the aqueous tsyor of the leshrymai film; or lachrymal substltutleb products. in the present description, "at least: onefftneans one primőré, and in particular, one.
The emulsion according to the invention is an oil-in-water type emuls on of wnich the aqueous phase comprises at least one stabilising polymer arid at least one mucomlmetle polymer, and the oily phase comprises at least one phospholipid-type lipid and at least one lipid other than phospholipid. A mucornimetic polymer may he a polysaccharide-type polymer, In particular selected from fö^jpiechäffdes,. '.iNd- .tefism -is- :ilyeans ο? polysaccharides, and mors-particularly from the glycosaminoglycans (SÁfíJ sód hyaluronic adds, these polymers* also known under the term acid mucopolysaccharides, may be characterised by a high water retention capacity giving them mucornimetic properties,
In particular, the polysaccharides comprise at least 5, ndtably at least W, particular at least 20 oslde or monosaccharide units,
Among the polysaccharides, mention may be made oft - dextrao sulfate, which is a compte* lri »«* « molecular weight from 4 to 500 kDa. , arabinogaiacum, wh-ch is a biopdymer constituted of arabinose and galactose monosaccharides, a natural cdP'iTQMce: or certain tsums and tne walH of certain mycobacterial ceils, heparin, in particular of molecular weight:^from 6 to So tvDa,, keratan sulfate, * chon droit in sulfate,· in particular with a motecusa; wesght of around 50 k!3a dermatan sulfate, and hyaluronic acid, which is a high-viscosity dissocnaude polymer, naturaicy present in numerous 'issues, including the conjunctive tissues and one or the main constituents of the extracellular
The latter may he obtained by extraction bom anima! timm-M? by »erM fermentation.
The mucomimeric poiyroer may no more preferably selected from the giycosaminoglycans arid hyaluronic acids and mixtures thereof. According to the invention, the mueomimeiic poiymer Is selected from the hyaluronic acids, dextran sulfate and chondroitin sulfate
The mucomimetic polymer may have a molecular weight from M-to 10,000 kDa, notably from 500 to 1.500 kDa, indeed around 1,000 kDa. in particular., the emulsion comprises a mucGntímeti^pölyfher content from Q.Ö1 to S% by weight relative to the total -weight of the emulsion, notably from 0.05 to 1.5% by weight., tn particular from 0.1 to 1% by weight, indeed from öl.IS· to O.S% by weight, and even more particularly of around 0.1% by 'weight.
Phospholipid-type lipids, mere commonly know?! as phospholipids*, ere lipids comprising a phosphate group, l.e., a unit of 2 fatty acids, glycerol and phosphate,.
They can include sphlngosine (serine » fatty acid), a fatty add. a phosphate and a htrpgen-containing alcohol or indeed two fatty adds, a glyceroi molecule, a· phosphate and a nitrogen-containing alcohol. in particular, the phospholipid may he selected from the phosphoscylglyccndes, also known as phosphacyigyfcsrois, phosphophmgoiipds, phosphonoshingoiipids, phosphogiycoiiplds and phosphosacharolipicis.
According to the invention, the phospholipid is selected from the lecithins, also known as phosphabdyk:holins, extracted from soya, egg or sunflower Lecithins are •preferably extracted from soya
Lecithin may be used alone or in combination, in particular, several different lecithins are present in the emulsion.
The emulsion may compose a phospholipid content from 0,01 to 3% by weight relative to the total weight of the emulsion, notably from 0.02. to 1% by weight, sn particuidr from 0 05 to 0,55¾ by weight, Indeed front O.Q?$ to 0.2% by weight, and even mors particularly:':«* around 0.1.% by-weight.
The emulsion comprises at least one lipid other than phospholipid, in particular a glyceride· type lipid, also known as glyceride.
The giycende-type lipid may bo a lipid from the class of acylgiycemds rn- glycerides, in particular selected from castor, soya, sesame, paraffin, lanolin, petroleum leiiy. corn, glycerine or monogiyesride or triglyceride· oils,
Particularly, said glyceride is a triglyeende, preferably a medium-chain triglyeende, of which the 3 hydroxyl groups of the glycerol are esterifled by fatty acids, having fron« 4 to 22 csîtion atoms, in particular having 8 to 22 carhop: atomsy preferably selected from çppric arid., caprylic acid and mixtures thereof.
The emulsion may comprise a content of lipid other than the phospholipid from 0.0). to $% by weight relative to the total weight of the emulsion,, notably from 0.05 to 2.8%, in particular from 0.1 to ).% by weight, indued fron- 0.15 to 0.5% Oy weight, and 'tMOPWi: particularly of around 0.2% by weight.
Particularly, the emulsion comprises a phospholipid other than the phospholipid / phospholipid weight ratio of Ö.l ie ID, notably from 0.2 to 5. In particular horn 0 5 to 2, indeed around 1.
The emulsion comprises at least one stabilising polymer, in partcular eh Ionic polymer, more particularly an anionic polymer.
According to the Invention, the stabilising polymer is selected from cellulose polymers.
The stabilising polymer may he selected from: poiyvloyialcohoi polymers, polysorbates and cellulose type polymers, notably metbyiceiluiose, etbyiceiiuiose, hydroxypropyi cellulose, carboxymethyi cellulose; in particular, tiro polymer Is carboxymethyi: cellulose.
The stabilising polymer Is Id particular a sodlym: polymer, ootabiy sodium carboxymethyi cellulose.
Sodium carboxymethyi cellulose may baye a general: formula; of fCbTvOaOHyoCHjCQONajvb with y, degree of sebstitutlpn, enabling solubilsation in. water, between 0,6 and 1, x between 1 end 2,4 |w:here xry:«2V and n between SO and 1,500.
Thé soluble: forms oldy: bave a viscosity from 5 to 2D00 cps In a 1¾ by weight solution, notably from 1000 to 2000 cps., indeed around 1S00 cps, Carboxymethyi cellulose may bavé à salt eontent reistive to the dry substance of st least |,5% and at most of 10,8% so as m correspond: with on® of the specifications of the buropean pharmacopoeia.
The stabilising polymer, rmtably ionic, may have a nsofecuiar weight from .17,000 to 100,000 g/moi.
The composition may comprise ä stabilising polymer content, irt particular ionic, from 0.01 to 5% by weight, notably from 0,05 to 2.5%, In particular from 0.1 to 1% by weight, Indeed from 0.15 to 0.5% by weight, and even mom partlculerly of around 0.2% by weight relative to the total weight of the composition.
The presence of tht stabilising poiymer, notably ionic, and In particular, carboxymethyi cellulose, notably sodium, enables the emulsion comprising at least rone phospholipid and a rnycornirnelie polymer to have a satisfactory stability. This stability may be noted notably by the she of the globules of the oily phase,, which remains substantially stable, notably an increase in sice of less than 10%, after 3 weeks.
The emulsion may exhibit a coalescence phenomenon, however, simple agitation may enable the globules to be mdnpersed.
The emulsion according to the invention may have a pH from 6 to 8, notably front 6.7 to 7.7, in particular from 7.0 to 7,5, Indeed of around 7.4.
The emulsion may particularly have a pH from 5,5 to 8, notablf Ifont ® td 717* In particular from 6,2 to 7,5, indeed of around ?,0. 'Particularly. the emulsion aecordingto the Ihveubon comprises a buffer medium or buffer. A buffer may be a phosphate, acetate dr citrate buffer. According to the invention, it Is a citrate buffer.
Particularly, the: citrate buffer may enable the stability of the emulsion TO: be improved,
Th·? emuidon according to the Invent!©© therefore Miva#ïs§s©.usly mm prises citrate ir. a suitable quantity to adjust the pH to the desired value.
The -emulsion is or oiNn-water type:* the oil part in the form of globules cimpfisíhi the lipid constituents previously described and öpti#halÍf'Sie.othöfi%dmptóhle:ánd/ör lipophilic constituents of the emulsion.
The small site of these glbbdles may participate: tin the poci stability of the emulsion, for the preparation of a preservativeOree emuimon, as defined below. preferably il to #§#·©! the emulsion should be able to pass through a CL22 :pm filter, a filter site generally used for stérilisation of The emulsion, ©lobules with a sire greater than 220 mm may pass through a 0,22 pm filter by temporarily modifying their shape, however, slowing the filtration process. . globules have a maximum:site^of less of less then oreoual to 160 nm.
The emuiaion according to the Invention: Is particularly suitable for topical use in the treatment or prevention of ophthelrnic diseases, notably as eye drops, enabling improved tolerance due to the fact that the emulsion Is staple without the use of surfactants, or at. least In a quantity small enough to be tolerated by the ocular surface.
According to a preferred empödlmenf, the present emulsion Is free from preservatives, notably chemical, used: alone or in combination, Said preservatives may in: particular hs selected from the list of products authorised by regulations, such as;: > quaternary ammoniums, notably henaalkonium chloride, alkyidimethyibentylaromanlum, cetrlmide, cetylpyridinlum chloride, Penaodecinlum bromide, leheoihonlum dhloh^ chloride, mercurial preseryatlyes, such as phehflomrcunc nitrate/acstMe/Porate, thiomersal, alconohc preservatives, such as eblocebiaanof, bemylic alcohol phenylefhanoi, phenyictPyiic alcohol, carboxylic a elds, such as sorbic acid, · phenols, in par|icpisr methyi/propyi parsben, amidines, for example chlorhexidine dîgluconate, and/or - fDTA,,: a chelating: agent that potentiates the efficacy of preservatives, Inc combination wffh at:least one preservative. in particular, ihe emersion is preferably free from F.OTA as such. "Free from preservatives” or '‘without preservatives". In the sense of the present" invention, means a preservatives and/or EDTA content of less than or equal to 10 pom, notably of less than or equal to 1 ppm, indeed equal to 0 ppm.
According to another aspect of the description, the composition may comprise at least orte preservative,, but preferably at a low concentration, for example at a concentration of less than or equal to 0 1% by weight, notably less than or equal to 0.05% by weight, indeed bf less than 0.01% by weight relative to the total weight of the emulsion.
The preservative is in particular present In the aqueous phase.
According to an advantageous embodiment of the invention, the emulsion is free from surfactants^ used alone ar In combination, hald surfactants are surfactants: typically used for the preparation of emulsions, in partrepisr in the field of cosrhetîcs and pharmacy m particular list of products âUtbô^téiV^gylttlO^^MÂ as: poly.sorbates, polyethylene glycols and derivatives thereof, polyöxyeíhyfene-40-sterat«, sorbitan esters, - : polyoxyethylene-poiyoxypropylene copolymers, * polyvinyl «icöhols, and pclyvtnylpitrolkione polymers "Free from surfactants" or "without surfactants" means, in the sense of the present invention, a content of less than or equalto 0.15¾ by weight relative to the total weight of the emulsion, notably of less than :0.015¾ by weight. Indeed equal to 0¾ by weight, itffeSphoiipds entering in: the composition of the emulsion according to the invention asprevinusly described, anti in particular lecithins, arg not theusuai surfactants employed m surfactants in the pmparatioo of emulsions in the field: of cosmetics or ^pharmacy, hi any event, they ere of course not excluded front the composition of tbs: emulsion according to the invention. •According to another embodiment: of the Invention, fbe ensulsfon may comprise at toast Ohé surfactant, preferably at a low concentration, he, at a concentration of less than or equal: to 0.5¾ by weight relative to the total weight of: the emulsion, notably of , less than or equal to by weight, indeed of less than 0.15¾ by weight.
According to a particularly preferred embodiment of the Invention, the emulsion Is freefrom surfactants and preservatives.
This can particularly limit, reduce or even avoid undesirable side effects, no :irriiation{s}, on the eye and/or mucsesmembraoes, in particular close to the eye.
Advantageously, the: emulsion according to the present Invention has a low viscosity dose to that of water, notably a dynamic viscosity of less than or equal to 10' 1 Pa.S, in particular from l,5.1Cf3::to B.lQ'h and more: particularly f?o:m 5:,10'3 to §.10>2:Pars, the emulsion according to the invention advantageously has a clarity as defmed by European Pharmacopoeia 7.0 hum 0 to 5000 MTU, m particular from 0 to 3000 NTU, and more particularly of around 200 to 700 MTU, indeed, around 500 NTU.
The emulsion accord ing to the invention is particularly suitable for a use m the form of stye drops, preferably of low viscosity as defined above and advantageously h rapid.
The emulsion according to the invention particularly suited for topical use 1rs the treatment or prevention of ophthalmic disorders, In paiTlcular as eye drops, may hove artificial tear properties, l.e. to have, once administered, a structure dose or identical to that of lachrymal liquid.
According to the invention, the emulsion is hypo-osmohu and has an osmolarlty from Ilf) to :180 mosmoi/i, particularly from 120 to .150 mosmol/i, indeed of around 125 rnosmol/i. A hypo osmolar osmolarlty may enable the hyperosmoUsmy generally noted by patients suffeung írom eye dryness to be compensated.
The person skilled in the art knows to adjust the osmolarlty of the emulsion according to the invention by the addition of an appropriate quantity of sail, m particular, sodium chloride, potassium chloride or sodium bicarbonate and/or potassium bicarbonate, preferably sodium chloride.
The Wüter content depends on the content of the other constituents of the emulsion according to the hweonon Preferably, in perde nier for an emuisson suitao-e for temiefe use in the treatment or prevention of ophthalmic disorders. In particular in the form of eye drops, the emulsion composes a water content of greater titan or equal to 90% by weigh? relative to the total weight of the emulsion, notably greater than 9S% by weight, in particular greater than 93% by weight, and more particularly greater than 99% by weight.
To this formulation, it is possible to add substances, particularly in the aqueous phase, participating in the restoration of the composition of the aqueous layer of the lachrymal film or lachrymal substitutes, such as: vitamin A, vitamin F, vitamin B12, albumin, sodium, potassium, ca 1 cicim, eh lor ide and bicarbonate ions, and buffer solution,
The composition or the emulsion may comprise oho or more active agents·, notably a therapeutically active agent. Tie's active agent is In particular intended M act on the eye or Is for ophthalmic usa.
This composition or ophthalmic emulsion may be used In the preparation of a product Intended for the treatment of ophthalmic disorders in combination with the restoration of the lachrymal film in dry eye syndromes, in particular Incorporating m active Ingredient with a therapeutic effect.
The active agent, notably for ophthalmic use, may be selected from antiseptics, antibiotics, anti-vimis, anti-mííamroacorles, antealiergy agents, antegiaueoma agents, antl-dryness agents, vasoconstrictors, anaesthetics, mydriatits, myotfcs, diagnostic products and products for the treatment of retinal disorders,
Amodgibe active ingredientsiforophthaimic use, mention may be maciaefr anaesthetics, such as Procaine, Cbiomptocaine, fidocaing,: Meplvscaine, Tst ra ca i ne, P ro paras a I ne, steroidal anti-inflammatories, such as Belhamethasone, Dexamethasorie, Fiuorometholone, Lotepredndi Etabonate, Medrysone, Prednisoipne, Rimexolone. Méthylprednisolone, Prednisone, Fiuocinolcme, triamcinolone; acetonide, non-steroidal anti-infiammatones,. such as Bufilpföfen, Suprofen, Diclofenac, Ketorolac, Aspirin, Indomethacln;, Ibuprofen, 'Mêptmm, imrnunomodulêtors, such as Cyclosporine, Azathioprine, Bromocriptine, Methotrexate, Dapsooe, Cyclophosphamide, Chlorambucil, Colchicine, anti-glaucoms agents, such as Dipiveffin, Fplnephryi, Apraclonldine, Brinmnidine, Betaxolol, Carteolol, Levobursoiol, Metipranoiol, Timolol, Carhachoi, Pilocarpine, Physosfigmine, Fchothlophate, Acetaaolarnide, Brin,toiamide, Doraolamide, Methattolamide, Latanoprost, Bimatopcost, Travoprost. Unoprostone, antibiotics and anti-infective agents, such as Cefotaxime, Ceftazidime, Cefuroxime, Cefatoiinc, Ceoogknhin, Ampicillin, Oxacillin, Ticarciíün, sodium sulfacetamide, Sulfísoxaxote. Buifamethoxaíoie, hieomycin, Gentamicin, Tobramycin, Amikacin. Morfioxaon. Ciprofloxacin, Ofloxacin, Gatifloxacin,
Levofloxacin, Moxifloxacin, Gramicidin, Polymyxin B,
Fryîhromydn, . Chbramphenkoi, TriOtetimprfm,: PxyteU acycline,
Vancomycift, and - ambvirels, such SS: Cidofovlr, .fo-mjivirsen, êoscarnst, Ganciclovir, Vsigancidovtr, Triflundlne, Acyclovir, anb-fungoi agants, Natamycln, Itraconazoî^.. iKetoconazole, Miconatole, Arophotedem I., Idusonatoie, flucytosine,
HoiWeybr/bthfer active Inifisdients and oíiisf cSsssosofthsfapouticsionfsn^yb^s o avisa ged.
According to a particular· aspect of tits description,: the comiposifion comprises essentially: mucomîmotk polymer, ,n particular hyaluronic acid, notably ai a content of «round 0.2% by weight relative to the iota! weight of the composition, phosphatidylcholine, in particular at a content of around 0.:1% by weight; relative to the total weight of the composition, at least one triglyceride, in particular cupric and/or caprylic acid, notably at accordant of around 0.1% by weight relatív®' te the total weight of the composition., stabilising polymer, in particular carboxyrr.etbyiceliulcse, notably at a content of around 0.1% by ’weight relative to the total weight of the composition, citrate and/or citric add, notably in order to adjust the pH to around ?., sodium chloride, notably in order to adjust the osmolarity, irtpertieuior to .180 mosmoi/l and >~ water.
Parrkularty, the present emulsion is sterilised without: using chemical sgempj, notably used as préservâtlve(s). This emulsion may in particular lies: sterilt m particular v<s 0.22 pm filtration
The emulsion, the composition or medicinái product may be packaged by aseptic "filling in a sterile environment, into unidose or Single dose-type: bottles, enabling Âë solution to be protected from any contamination during use, notably as described id the foiiowmg documents WO 2008/0Í55G5, US 20QS/Ö294347. US 2007/0210121, £P 2 OSS 068, PR 2 816 600. US 5,232,68? or FR 2 873 358, or ip any other bottle intended for topical administration of medicinal products enabling the use of preservatives to be avoided.
According;· to one of its aspects, the description relates to so assembly comprising a container as described above and an .emulsion according to the Invention.
Recording to a particular embodiment, the preservative-free emission présent in the assembly is sterile and may remain sterile, for example for at least three months, notably at least six months. In particoiaratleast one year, indeed even three years, before opening.
Ones the bottle is opened, and depending on the type of bottle, the emuision may bo used for 1 month, indeed 3 months,
According to another of its aspects, Urn object of the inyentionis a pharmaceutical composition or a módiéinál product .comprising, or consisting of, an emulsion: asbascrihed above, in particular Intended to treat or to prevent, ocular dryness, allergies and/or mflammstioo of the eye, in particular linked to ocular dryness.
According to mother ai ls a$pg<£s, the' object of thmimmifon % the me of a imrnpdsltlem according to tm mvétéon fm th# preparation of « pharmaceutical composition or of a medicinal product, IP particular Intended to treat or to prevent ocular dryness, allergies and/onnflammatlon of the eye, in part«cui<u linked tó ocular dryness.
According to soother di rts aspects, the object of the invention is sp; emulsion or a composition as defined ahoy® fttrtber ePfoptislOg ah active compound. In particular to act on the aye.
According to yet another of its aspects, the object of the invention Is the use of a composition or an erndlsSep: according m the: invention as a vehicle for an active compound, in particular intended to act oh the eye.
When this emulsion is used as a vector, it can enable the concentration of the active Ingredient or the dosage., the number of applications and/or the time between two applications to be reduced.
Without wanting to be bound by this theory., this can corns from the fact that said emulsion, perhaps due to its viscosity and its rrmcoadhesive properties, improves; residence time, and thus increases the proportion of the active Ingredient that may be delivered to the target,
According to yet another of Its aspects, the Invention alsorelates to the use of an emulsion or a composition according to the invention as an agent to restore and/or replace the lachrymal film.
The Inventicm relates in particular to an emulsion as defined above and in the exampies, for Its use In the treatment or prevention of ophthalmic disorders, more particularly in the treatment or the prevention of ocular dryness, allergies and/or inflammation of the eye.
The description relates to a method for the treatment or prevention of ocular dryness, allergies and/orInflammation of the eye IP e subject repuirlng such treatdient, winch consists of applying to the eye or to both eyes an appropriate puarrtity of the emulsion according to the invention as defined above end in the examples.
This emulsion is advantageously applied in the form of droplets that are allowed to fall in contact with the eye, according to the usual application methods for ophthaimia: •compositions, mors particularly eye drops. The number of drops applied for each application is generally not limited in so far as anexcessnf smulslon wili he eliminated by the natural bfinkmg of the eyelids over the eye. The number of doily applications will depend on the needs specific to each subject
However, In SO far as the composition could contain an active ingredient as previously defined, the number of dropsapplied:and the numherof dally applicatlOM will depend on the ingredient that will: be delivered with the emulsion according to the invention.
According to another of its aspects, the description also further relates to the use of a stabilising polymer, possibiy inmmbinatlon with a phospholipid, as a siabiilsingagent for m emulsion comprising a lipid in the hydrophobic phase, a polysaccharide with mocömímeííc or mucoadhesive properties in the hydrophilic phase, combined in an aqueous phase with the help of at least one phospholipid and at least one ionic polymer.
According to yet another of its aspects, the description relates to the use of a stabilising polymer, optionally in combination withm phospholipid, as a stabilising agent for an emulsion comprising: * A lipid other than the phospholipid; in the hydrophohic phase. s mpeomimstie polysísr !γϊ the aqueous phase, in particular at a significant ievei, notably as defined above.
According to another of its aspects, the invention relates to a method of preparing ars oil-in-waier emulsion as: defined according to any one of daims 1-:U, comprising the follows ng: steps: a| mixing a phospholipid seiected from lecithins and a lipid other than the phospholipid, notably at a temperature greater than 3ö*€, b|: dissolving a mucomlmetic polymer selected from hyaluronic acids, destran sulfate and chondroitin sulfetelo « hoffep pstahiy citrate, c|dlssoivihg a stablfisiog polyieeeseteetediroïn cellulose polymers in the aqueous phase of step is), d i dispersing the oily phase of step a) in the aqueous phase of step c) by agitation, e) controlling and adjustingthe pH, notably by adding respectively an alkali or an add, in particular rhe alkaiino or acid form of the compound form Ing; the ^buffer, and/or controlling and adjusting the osrnolarity, and Π sterilising the emulsion, w particular by filtration of the emulsion: obtained, notably using a 0.2.?. pm filter, in particular by maintaining it at a temperature greater than 30':C.
In particular, the agitation of step d) is a strong agitation in order to bit alp: Smalh sited drops, in particuiar es defined m the present description This agitation may be carried out with a homogemser.
Said method may further comprise a packaging step. Ip particular ip sterile peekaging, and yet more particularly In packaging enabling the emulslcm to be kept sterile, notedly the packaging is es described above. in particular, step a) Is carried out by mixing the lipid other than f he phospholipid, the phospholipid-type lipid and distilled water, notably by heating to a temperature greater than 30‘C, under agitation, until a homogeneous phase Is obtained.
The ratio of phospholipid-type lipid to iipkl other than phosoholipid may be from 1:S to 1:3..
The total lipid content In distilled water may be around to the fosai weight of the composition.
The emoisicn obtained in step a) may be sterilised by filtration, in particular using a 0.23 pm biter. The temperature may be greater than 3<TC.
Step b) may be carried out by dissolving the mucomlmetlc polymer In a buffer, notably citrate, and heating it, notably to a temperature greater than 30"C.
During step c/ it is possible to control and adjust the pH and/or the osmolarity by respective addition of citrate or citric acid and/or sodium chloride.
When It Is stated that the “temperature may be greater than SOT", it may more fartieulariy go from 32 to 45*C, noiabiy from 35 to 43*C, indeed from 37 to d2::C.
Particularly, (his emulsion is sterilised by filtration, in particuiar over :a microbiological filter with a filtration threshold of Ù.22 pm, in j>p {Polypropylene}, pgg {PoiyftherSuifone}, PTFE (PolyTetraFluorokthyiene), PUT (PoiyEster), PC {PölyCáfbonate| or any other filter enabling sterilising filtration to be performed.
According to a variant of the implementation of the method, it is possible to further add during step a) to e) a surfactant.
According $p s wSml if the ;efmethod, K is possible during %pp %f tu e) to -m m active iogrMisotförophthofm^ ose, a prmmtm máim m qgtrit fcnteriog in the composition of ihe aqueous phase of the lachrymal film.
Of course, the various characteristics tfefosed in the present âescrtptiM may fee rumplned with each other,
The following examples are given for iltetIMiv# pm$m$ pfém iwmtim, iXAMfHt
The examples Mow are eye drops based m οϋ-In-water emulsion and a mucomimetic polymer. In particular intended turestore the various layers of the iachrymai film ip patients suffering from dry eye syndrome. They are prepared with the following ingredients given for a centesimal romptrslfion, These formulae have a pH of around ?. f end are hypotonic to tears.
Comparative example i:
OikMhiEC
Triglycerides ö.OS%
Lecithin 0.1%
Ci^ndmitin sulfate 0.2%
Polyvinyl aicohoi '0-2%
Citric acid QTISM
Oodlurp citrate O-OSfd
Sodium chip ride q.s.
Distilled wafer q.s.
Comparative example 2: liÉÜ
Triglycérides 0.2%
Lecithin 0,:i%
BiOMdCillMf
Sodium hyaiuronais Ü.2%
Polysorhate 0,2%
Citnc add Ö.0SM
Sodium citrate O.OSlvi
Sodium chloride q.s.
Distilled water q.s.
Example $;
Qiiv.oMsy.
Triglycerides (),0,¾
Lecithin 0.1% âffilffiMiiliœ
Dextran sulfate Ù3%
Sed i urn hydf05«yp«Opy{ me thy ice 1 lu lose 0, Z% Citric acid Q.Q5M
Sodium citrate 0,0.51$
Sodium chloride q.s.
Distilled water q%
Comparative exemple 4;
Ojly.sh3se.Î
Triglycerides CL0S%
Lecithin 0,i%.
Heparin 0.2% : Pq lyvIhylpyrrolMô ne 0,1%
Sodium carôoàymethylceiiylose 0,1%
Citric add 0.050!
Sodium citrate 0.051$
Sodium chloride q.s.
Distilled water q.s,
Comparatlve example S; QM.8hâ!&amp;·
Triglycérides 0,05%
Lecithin 0J%:
Aqueous phase:
Sodium alginate 0S%
Polyvinyl alcohol '0,1%
Sodium carhexymethyleelluioee 0.2%
Citric seid O.OSM
Sodium citrate CIOSM
Sodium chloride q.s>
Distilled water q,s<
Example S:
Oily phase:
Triglycérides 0,1%
Lecithin 0,1% âSMôUdPàdiq:
Sodium hyaioronate 0.2%
Sodium careoxymethyiceildose 0,1%
Citric acid (tOSM
Sodium citrate 0.051$
Sodium chloride q.s.
Distilled water q.s. ÊKâmpi® ?i
Triglycerides 04% lecithin 0.1%
Sodl um hya ! u ro n ats 0.2 %
Sodium carbd^mgthylcsllubsá 0,0S% Pölyvínyí: alcohol 0.1%
Citric acid Ö.GSM
Sodium citrate 0.ÖSM
Sodium chloride q,s.
Distilled water q.s.
Comparative example Si Oyv.odjte:
Triglycerides 0,05% lecithin 0.:.0% ÄQj;mOLB|duee;:
Sodium hyaloronate 0,2%
Polyvinyl alcohol 0.2%
Citric acid Ö.ÖSM
Sodium citrate 8.05!%
Sodium chloride q,$.
Distilled water q.s.
Comparative example 9:
Trigiy ce rides 0.2 %
Lecithin 0.1% âaassysjgûs^
Sodium hyaiuronate 0.2%
Poiysorfcate 0.1%
Citric add 0>0SM
Sodium citrate D.8SM
Sodium chionde q.s.
Distilled water q.s^ example 10:
Triglycérides (5,85¾ lecithin 8,1¾ läSsSÄlllEi
Sodium hyalumeate 0.2¾ Söd iym hydrexyρrópyimetbyi'Celfubse 0.2¾ Citric seid 0.0881
Sodium citra ta 0,ÖS fvl
Sodium chloride o,s.
Distilled water q.s.
Lxsmplè M:
Trlglycsddes Qii.% .Lecithin 0,1¾
Sodium -hyâiyrenate 0,2%
Sodium cardoxymethyIcelkdose 8,1 %
Sodi'ym'hydfoxypiropylmethykell.utose· 8;.1.% Cltrleacid O.OStvi
Sodiym citrate O.OSIvî
Sodium diiodde q,s.
Distilled water q.s.
Example 12:. Qÿy.Æm..
Triglycerides 0,8$% teothm 0.î% cnîiyoysjMyîïe:
Sodium hyaiuronate 0,2¾
Sodium carboxymethylcejyose 8.1%
Polyvinylpyrrolidone 0. 1%
Citric acid O.OSIVt
Scs di « m citrat e 0, DS M
Sodium chloride q,s,
Distîlbd water «.<;.
Sxampio ISt
Oily phase: T rigly cerîdes 0;ÔS% lecithin 8,1¾ émsmjipJmm
Sodium hyaluröoate 0.2%
Sod lu m oar hoxy methy ;εό Ily íosé Ô. 1%
Polyvinyl alcohol Q.1%
Citric-add 0.0§Μ
Sodium citrate 0.05M
Sod i u m. ehfocid e <3 > s,
Disti I led wa ter q , s.

Claims (3)

Szabadktai iglsypnnókSubotica fortunes 1, TartAsflöszer meÄs οΐφδ^νίζορη eimilÄ amely giöhóámak maximálta méreté 220 £i- ÏMQm^m&amp;t tartalü» - legalább egy, a MateâKsà^k, d^tÄ^rffätÄkoÄÄ5*S'ZsilÄkfeil vfcÄMxt«!^ mimetikus pol Imert, ~ legalább egy, a ledünek közül választott, fbszfoiipid tlpusu lipidet, -legalább egy, a. fosxfalipiâîôJçXûfeb^^lipife,, ~ iegáláib «gÿ5 a cellulóz polimerek közti választott, stabilizáló polimert., - citrái poffer közegei, vizet, Membetegslgek kezdésében vagy megelőzésében történő alkalmazásra '%. ßmolai-a-vizhen emulzió az 1. igénypont szerinti aikdumzásra, amely továbbá egy szemészéű bikáidurzásű batóanyagoi tanaimáz, :3* Az emulzió az I. vagy 2. igénypont szerinti alkalmazásra a szemszárazság, ajk Ikgiák ésruágy szémgyuliadás kezelésében vagy megelőzésében/'történő alkalmazásra, 4 Az emulzió az előző igénypontok bármelyike Szeri mi alkalmazásra, ahol a mukoroúneíikus polimer iarlálóí-n az emulzió összes tömegére vonatkoztatva 0,01 tömegektől 5 tömcg%*ig változik, fi Az emnlzm az i-4. igénypontok bármelyiké szetmti alkalmaMsra* aböl a tósz-lölipiö tértalöm az en na dó összes tömegére vonatkoztatva 0|tl töm^%~tÖl 2 tömeg%"ig v|k tozlk, 4 Az emulzió az 1-5. igénypontok bármelyike szerinti alkalmazásra, ahöl a isaz-IblipldtÓI kilönbözo Epid tartalom az emulzió összes tömegére vonatkoztarva 0,01 tömeg%» -tói 5 tömeg%-ig vá!tozlk.1, TartAsflszer meÄ ïΐφδ ^ νίζορη eimilÄ which gióóamma maximized to size 220 £ i- ÏMQm ^ m &amp; t content »- at least one, MateâKsà ^ k, d ^ tärffätäko5 * S'ZsilÄkfeil vfcÄMxt«! Mimetic pol Imert, ~ at least one lipid selected from the glossy lipid, at least one, a. fosxfalipiâîôJçXûfeb ^^ lipife, obtained from the selected stabilizing polymer of cellulose polymers., - citrate buffer media, water, for use in the onset or prevention of Membetegggg '%. ßmolai-a-water emulsion for alumina according to claim 1, further comprising an ophthalmic bicarbonate-borne drug substance: 3 * The emulsion for use according to claim 1 or 2 for use in the treatment or prevention of eye dryness, lips of icicles, and lung ophthalmic inflammation / '; The emulsion of any one of the preceding claims, wherein the mucorose-like polymer is modified from 0.01 to 5% by weight based on the total weight of the emulsion, i.e. i-4. A method according to any one of claims 1 to 5, wherein the emulsion for use according to any one of claims 1 to 5, wherein: the isoblipidopic acid ejection epid content ranges from 0.01% to 5% by weight of the total weight of the emulsion. 7. Az emulzió az 1-6, igénypontok bármelyike szerinti alkalmazásra, ahol a cellulóz polimert a mdilmellulóz, mii-cellulóz, hidroxi-propil-eeltulóz és karbozkmetikcelluiiz közöl választjuk.The emulsion for use according to any one of claims 1 to 6, wherein the cellulose polymer is selected from mdilmellulose, cellulose, hydroxypropylcellulose and carboxymethylcellulose. 3. Az emulzió a 2-7. igénypomok i&amp;melylke szentöl alkalmazásra, ahol a stabilizáló pollmer tart^om az emulAó összes tömegére vonatkozóivá 0,01 iörneg%~i6i S tő- meg%~ig változik.3. The emulsion is shown in Figs. 2-7. I use for the use of i &amp; nk sac, where the stabilizing pollmer content changes to 0.01% by weight of the total weight of the emulo. 9. Az emulzió az 1-8. igénypontok bármelyike szerinti alkalmazásra, azzal fék îtiwm^ftOKV az emulzió viszkozitása 10'1 Pa,s vagy kisebb. Ü, Az emulzm az 1-9. igénypontok bármelyike szerinti aikaimazásra^ azzal |éi~ femezve, ln>gy az érnnizlo átlátszósága 0 - 500C NTU. 1L Az orrtulzió a 2-S. igénypontok bársndyike szermti alkalmazásra, amelynek pH értéke 5,5 - 8, IS, .Eljárás az Μ1, igénypontok bármelyike szerinti olajm-vizbeu tmuMé előállít lására, amely a kővetkező tépéseket logIárja magában: a) égy, a feoitmok közöl választott, tbszMipid típnsú Mpid és egy foszfoHpidtöl különböző li pid összekeverése, b) egy, a biálnronsavak, dexiían-'Sznlíát és kondroitin-szulíat közöl választott, mukornimeti- kns polimer feloldása ertrát paílerbeo, e) egy, a ceilüiőz polimerek közöl válásaiéit, stabilizáló polimer feloldása a b) lépés vizes lázi sóban, d) uz a) lépés olajos fázisának diszpegalása keveréssel a e) lépés vizes fázisában, ©) a pH ellenőrzése és beállítása, nevezetesen egy bázis vagy egy sav megfelelő hozzáadásával és/vagy az ozmolaritás ellenőrzése és beállítása, és i) az emulzió sterilizálása, előnyösen szűréssel 0,22 um szorő aikálutazása segítségévei.9. The emulsion according to claims 1-8. For use according to any one of claims 1 to 5, wherein the emulsion has a viscosity of 10'1 Pa, s or less. Ü, The emulsion is from 1-9. A method according to any one of claims 1 to 4, characterized in that the viscosity of the screen is 0 - 500C NTU. 1L Orthosis is 2-S. Claims for use in the preparation of an oily water according to any one of claims 1 to 1, comprising the following tears: (a) be selected from the group consisting of fungi, mipid type Mpid; and mixing a phosphorus other than a lipid, b) dissolving a muconimeter polymer selected from the group consisting of bilonic acids, dexylan-zylate, and chondroitin sulfate, e) eradicating the dissolution of stabilizing polymers, step b) of cylylic polymers step b) d) dispersion of the oily phase of step a) by stirring in the aqueous phase of step ae, ©) checking and adjusting the pH, namely by the appropriate addition of a base or an acid and / or controlling and adjusting the osmolarity, and i) the emulsion sterilization, preferably by filtration with a 0.22 µm passage of time.
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JP2013525335A (en) 2013-06-20
ES2638868T3 (en) 2017-10-24
EP2560616A2 (en) 2013-02-27
FR2962044B1 (en) 2013-02-22
EP2560616B1 (en) 2017-07-19
WO2011131765A2 (en) 2011-10-27
JP5917490B2 (en) 2016-05-18
US9801899B2 (en) 2017-10-31
PT2560616T (en) 2017-08-30
PL2560616T3 (en) 2017-12-29
DK2560616T3 (en) 2017-10-16
FR2962044A1 (en) 2012-01-06
WO2011131765A3 (en) 2012-02-23
US20130156867A1 (en) 2013-06-20

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